Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis

The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis, are lipid mediators of smooth muscle constriction and inflammation, particularly implicated in bronchial asthma. LTC4 synthase (LTC4S), the pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa integral nuclear membrane protein that belongs to a superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism that includes 5-lipoxygenase-activating protein, microsomal glutathione S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref. 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate derived from arachidonic acid through the 5-lipoxygenase pathway. In contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate glutathione to xenobiotics. Here we show the atomic structure of human LTC4S in a complex with glutathione at 3.3 A resolution by X-ray crystallography and provide insights into the high substrate specificity for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The LTC4S monomer has four transmembrane alpha-helices and forms a threefold symmetric trimer as a unit with functional domains across each interface. Glutathione resides in a U-shaped conformation within an interface between adjacent monomers, and this binding is stabilized by a loop structure at the top of the interface. LTA4 would fit into the interface so that Arg 104 of one monomer activates glutathione to provide the thiolate anion that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). These findings provide a structural basis for the development of LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl leukotriene ligands whose stability and potency are different and by multiple cysteinyl leukotriene receptors whose functions may be non-redundant.     

利用EA建模加强机构信息安全风险管理

当前很多机构信息系统都普遍存在保护措施与其保护信息价值不匹配的情况,导致过度保护或保护不足。这种情况主要是源于安全目标与机构业务目标不完全符合、安全需求获取不规范、难以判断风险管理中是否应用了合适的安全控制以及成本是否平衡。对此,该文提出了在信息系统开发生命周期(information system development life cycle,SDLC)内利用机构体系结构(enterprise architecture,EA)这一管理工具进行安全目标分析、安全需求获取、风险管理等,开发符合机构管理目标的安全信息系统,以加强机构的信息安全和风险管理。利用EA模型的方法能提供一种机构层面的整体性安全描述和分析结果,在整个SDLC内为信息系统的安全开发和管理提供指导和依据,特别是在风险管理中,为进行安全控制选择和成本平衡的决策提供了一个有效的判断机制与依据。     

Forecasting for the generation of trading signals in financial markets

In this paper we show that optimal trading results can be achieved if we can forecast a key summary statistic of future prices. Consider the following optimization problem. Let the return r_i (over time i=1, 2, ..., n) for the ith day be given and the investor has to make investment decision d_i on the ith day with d_i=1 representing a ‘long' position and d_i=0 a ‘neutral' position. The investment return is given by r=Σⁿ_i=1r_id_i−cΣⁿ⁺¹_i=1∣d_i−d_i−1∣, where c is the transaction cost. The mathematical programming problem of choosing d₁, ..., d_n to maximize r under a given transaction cost c is shown to have an analytic solution, which is a function of a key summary statistic called the largest change before reversal. The largest change before reversal is recommended to be used as an output in a neural network for the generation of trading signals. When neural network forecasting is applied to a dataset of Hang Seng Index Futures Contract traded in Hong Kong, it is shown that forecasting the largest change before reversal outperforms the k‐step‐ahead forecast in achieving higher trading profits. Copyright © 2000 John Wiley & Sons, Ltd.     

圈的推广Mycielski图的圆色数

Mycielski图是1955年由Mycielski提出来的．任给一个图G和一个非负整数m,G的推广Mycielski图μm(G)是G的Mycielski图的一个自然的推广．推广Mycielski图的性质以及它们的点色数、圆色数和分数色数等已有许多研究．本文研究圈的推广Mycielski图的圆色数．定义Cn为n个顶点的圈．对任意非负整数m和大于2的整数n,本文确定了图μm(Cn)的圆色数,同时还得到了图μm(Cn)-v的圆色数的一些结果．     

Modeling an Elastic-Demand Bimodal Transport Network with Park-and-Ride Trips

This paper presents a network equilibrium formulation for modeling commuters＇ travel choices in a bimodal transport system with park-and-ride （P＆R） trips while the total demand is elastic to the congestion level of the network. A super-network approach is adopted in the proposed model. It is assumed that commuters＇ trips are categorized into two types, auto mode only and a combined mode with both auto and transit modes. The former is referred to as the pure mode trip and the latter as the P＆R mode trip. The proposed model simultaneously considers the commuter＇s choice of the pure mode versus the P＆R mode, the choice of parking location for the pure mode, the choice of transfer point for the P＆R mode, as well as the route choice for each mode. The demand elasticity of transport system, the capacity constraints of transport facilities, and the congestion interaction throughout the super-network are also explicitly incorporated into the proposed model. The results of the numerical experiment show the following key findings： （i） traditional parking/P＆R models may overestimate or underestimate travel demand distribution over network; （ii） parking/P＆R, transit scheduling, and carpooling schemes bring significant impacts on commuters＇ travel behavior and network performance; and （iii） different transport policies may be to some extent mutually substituted .     

带预制空心板的半刚性复合节点的弯矩和转动能力预测方法

对带预制空心板的复合梁-柱节点结构性能的研究目前是新颖且无暂行的可用来预测其弯矩和转动能力的计算方法．在本文中,在足尺度测试和参数分析的基础上,提出了预测该类型复合节点的弯矩和转动能力的设计公式．对所提计算方法和足尺度测试结果进行了对比,结果吻合良好．     

Inactivation of the p53 pathway in retinoblastoma

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.     

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1

The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs-PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.